Polar Hydrophilic Prodrugs of Amphetamine and Other Stimulants and Processes for Making and Using the Same

ABSTRACT

Disclosed are amphetamine prodrug compositions comprising at least one non-standard amino acid conjugate of amphetamine, a salt thereof, or a combination thereof, and methods of using the same.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/477,616, filed Jun. 2, 2009, which application is a continuation ofPCT/US08/53363, filed Feb. 8, 2008, which claims priority to and benefitof U.S. provisional patent application No. 60/888,870, filed Feb. 8,2007.

BACKGROUND OF THE INVENTION

The present technology describes, in general, novelprodrugs/compositions of the stimulant amphetamine (i.e.,1-phenylpropan-2-amine) as well as polar hydrophilic conjugates ofamphetamine, salts thereof, other derivatives thereof, and combinationsthereof. Additionally, the presently described technology also relatesgenerally to the methods of making and using these newprodrugs/compositions.

Stimulants, including amphetamine and its derivatives, enhance theactivity of the sympathetic nervous system and/or central nervous system(CNS) and are prescribed for the treatment of a range of conditions anddisorders predominantly encompassing, for example, attention deficithyperactivity disorder (ADHD), attention deficit disorder (ADD),obesity, narcolepsy, appetite suppression, depression, anxiety andwakefulness.

Attention deficit hyperactivity disorder (ADHD) in children has beentreated with stimulants for many years. However, more recently, theincrease in the number of prescriptions for ADHD therapy in an adultpopulation has, at times, outperformed the growth of the pediatricmarket. Although there are various drugs currently in use for thetreatment of ADHD, such as methylphenidate (commercially available from,for example, Novartis International AG (located in Basel, Switzerland)under the trademark Ritalin®) and non-stimulant atomoxetine(commercially from Eli Lilly and Company (located in Indianapolis, Ind.)as Strattera®), amphetamine has been the forerunner in ADHD therapy.Moreover during classroom trials, non-stimulants have been shown to beless effective in improving behavior and attention of ADHD afflictedchildren than amphetamine derivatives.

Initial drug therapy for ADHD was limited to fast acting immediaterelease formulations of stimulants (e.g., Dexedrine®, puredextroamphetamine sulfate, commercially available from Smith Kline andFrench located in the United Kingdom) which triggered an array ofpotentially undesirable side effects including, for example, fastwear-off of the therapeutic effect of the stimulant active ingredientcausing rebound symptoms, cardiovascular stress/disorders (e.g.,increased heart rate, hypertension, cardiomyopathy), other side effects(e.g., insomnia, euphoria, psychotic episodes), addiction and abuse.

Behavioral deterioration (rebound/“crashing”) is observed in asignificant portion of children with ADHD as the medication wears off,typically in the afternoon or early evening. Rebound symptoms include,for example, irritability, crankiness, hyperactivity worse than in theunmedicated state, sadness, crying and in rare cases psychotic episodes.The symptoms may subside quickly or last several hours. Some patientsmay experience rebound/crashing so severe that treatment must bediscontinued. Rebound/crashing effects can also give rise to addictivebehavior by enticing patients to administer additional doses ofstimulant with the intent to prevent anticipated rebound/crashingnegative outcomes and side effects.

Stimulants, such as methylphenidate and amphetamine, have been shown toexhibit noradrenergic and dopaminergic effects that can lead tocardiovascular events comprising, for example, increased heart rate,hypertension, palpitations, tachycardia and in isolated casescardiomyopathy, stroke, myocardial infarction and sudden death.Consequently, currently available stimulants expose patients withpre-existing structural cardiac abnormalities or other severe cardiacindications to even greater health risks and are frequently not used orused with caution in this population. It is notable, however that thecardiovascular effects of stimulants, for example on heart rate andblood pressure, is dependent on the administered dose. As a result, atreatment which maintains the lowest effective stimulant bloodconcentrations for a therapeutically beneficial duration is believed todemonstrate fewer cardiovascular risks/side effects.

Amphetamine and many of its derivatives (e.g., methamphetamine,3,4-methylenedioxy-methamphetamine/“Ecstasy”) are widely abused forvarious purposes such as euphoria, extended periods ofalertness/wakefulness, or rapid weight loss or by actual ADHD patientswho developed excessive self-dosing habits to prevent rebound symptomsfrom manifesting, for example, in anxiety or depression. The effectsdesired by potential abusers originated from the stimulation of thecentral nervous system and prompted a Schedule II or even Schedule Iclassification for amphetamine (d- and l-amphetamine individually andany combination of both are Schedule II) and certain derivatives thereofafter passage of the Controlled Substance Act (CSA) in 1970. Bothclassifications are defined by the high propensity for abuse. ScheduleII drugs have an accepted medical use while Schedule I substances do notpursuant to the CSA. So far, all amphetamine products, includingcompositions with sustained release formulations and prodrugs thereof,are obligated to include a black box warning on the drug label to informpatients about the potential for amphetamine abuse and dependence.

It has been observed in the conventional art that most side effects ofamphetamines are caused by a large initial spike in blood concentrationof the stimulant which quickly erodes to levels below therapeuticeffectiveness (typically within 4-6 hours). As a consequence, the highpotency of dextroamphetamine (d-amphetamine) was subsequently modulatedby a series of new drugs with increasingly sustained release profilesachieved by delivering amphetamine more slowly into the blood streamwith the goal to create safer and less abusable treatment outcomes andregimens. The methods and technologies for generating smaller spikes indrug blood concentrations include, for example, use of mixed salts andisomer compositions (i.e., different salts of d- and less potentl-amphetamine), extended/controlled/sustained release formulations(e.g., Adderall X® commercially available from Shire U.S., Inc. locatedin Wayne, Pa.) and, most recently, prodrugs of amphetamine (Vyvanse™also commercially available from Shire). The ideal drug treatment optionshould produce stimulant blood concentrations within a narrowtherapeutic window for an extended time duration followed by a prolongedfade-out period in order to minimize cardiovascular stress andbehavioral deterioration, and would also exhibit anti-abuse properties.

Besides immediate release formulations, newer sustained releaseformulations have been developed with the objective to provide atherapeutic treatment option that offers the convenience of a singledaily dosing regimen versus multiple quotidian administrations. Suchformulations also have the objective of imparting or rendering aeuphoric response. Sustained release formulations commonly consist ofdrug particles coated with a polymer or polymer blend that delays andextends the absorption of the active drug substance by thegastrointestinal tract for a relatively defined period of time. Suchformulations frequently embed the therapeutic agent/activeingredient/drug within a hydrophilic hydrocolloid gelling polymer matrix(e.g., hydroxypropyl methylcellulose, hydroxypropyl cellulose orpullulan). This dosage formulation in turn becomes a gel upon enteringan acidic medium, as found in the stomach of humans and animals,thereupon slowly effusing the therapeutic agent/active ingredient/drug.However, the dosage formulation dissolves in an alkaline medium, asfound in the intestines of humans and animals, concurrently liberatingthe drug more quickly in an uncontrolled manner. Some formulations, suchas acrylic resins, acrylic latex dispersions, cellulose acetatephthalate, and hydroxypropyl methylcellulose phthalate, offer improvedsustained release in the intestines by being resistant to acidicenvironments and dispensing the active ingredient only at elevated pHvia a diffusion-erosion mechanism, either by themselves or mixed withhydrophilic polymers.

Sustained release formulations have been moderately effective inproviding an improved and extended dosage form over immediate releasetablets. Nonetheless, such formulations are potentially subject toinconsistent, erratic or premature release of the therapeutic agent dueto failure of the polymer material, and they also usually allow easyextraction of the active ingredient utilizing a simple physicalprocedure. Since single daily dose formulations contain a greater amountof amphetamine than immediate release formulations, they are moreattractive to potential abusers, consequently making the extractabilityof drug substance an additional undesirable property. It is also, atleast in part, a reason for increased drug diversion, especially evidentby selling or trading of medication by school children who are ADHDpatients and in possession of sustained release amphetamine capsules.The obtained stimulants are then abused by classmates without thedisorder by either ingesting high doses or snorting the drug materialafter crushing it.

U.S. Pat. No. 7,105,486 (to assignee New River Pharmaceuticals,hereinafter the “'486 patent”) appears to describe compounds comprisinga chemical moiety (namely L-lysine) covalently attached to amphetamine,compositions thereof, and methods of using the same. Allegedly, thesecompounds and their compositions are useful for reducing or preventingabuse and overdose of amphetamine. The '486 patent also describes thatusing any amino acid other than l-lysine (Table 46) will not give riseto the same in vivo properties demonstrated by l-lysine-d-amphetamine(Lys-Amp, Vyvanse™). Additionally, since lysine is a natural andstandard amino acid, the breakdown of the new prodrug occurs faster thandesired to reduce the side effect profile. Thus, quick release ofamphetamine from such standard amino acid conjugate compositions maycause an increase in blood pressure and heart rate found in otherconventional stimulant treatments. As a result, there still exists aneed within the art for a safer dosage form of amphetamine, andtreatment regimen that is therapeutically effective and can providesustained release and sustained therapeutic effect.

BRIEF SUMMARY OF THE INVENTION

In general, the presently described technology in at least one aspect isfor example, a slow/sustained controlled release composition ofamphetamine, in prodrug form, that allows slow/sustained/controlleddelivery of the stimulant into the blood system of a human or animalwithin a safe therapeutic window upon oral administration. At least somecompositions/formulation of the current technology can lessen therebound effect, cardiovascular stress, addiction/abuse potential and/orother common stimulant side effects associated with amphetamine andsimilar compounds. Such compositions may also increase the duration oftherapeutic efficacy, ease of application, patient compliance and/or anycombination of these characteristics when administered, in particular,orally.

Thus, the presently described technology provides compositionscomprising at least one stimulant chemically attached to a polarhydrophilic ligand, a salt thereof, a derivative thereof, or acombination thereof, which can diminish or eliminate pharmacologicalactivity of the stimulant until released in vivo in a human or ananimal. The stimulant chemically attached to (preferably covalentlyattached to) the polar hydrophilic ligand of the present technology isthe stimulant in a prodrug form, which can be referred to as a polar,hydrophilic stimulant prodrug, and can be converted into its active formin the body by normal metabolic processes. Although not wanting to bebound by any particular theory, one or more polar hydrophilic conjugatesof the present technology are believed to be safer than other sustainedrelease forms of amphetamine by providing controlled blood levels for aprolonged period of time, thus preventing the rebound effect,cardiovascular stress and euphoria associated with conventionalstimulant treatment options. One or more polar, hydrophilic stimulantprodrugs of the present technology are stable in tests that simulateprocedures likely to be used by illicit chemists in attempts to releasethe stimulants.

The presently described technology further provides methods ofcontrolled therapeutic delivery of amphetamine compositions by oraladministration. Release of amphetamine following oral administration ofthe polar hydrophilic conjugates of the present technology can occurgradually over an extended period of time thereby eliminating unintendedelevations (e.g., blood level concentration spikes) of drug levels inthe bloodstream of a human or animal patient. Again not wanting to bebound by any particular theory, it is also believed that such spikes inblood levels can lead to a euphoric drug “high” and cardiovasculareffects like increased blood pressure and heart rate. Additionally,sustained blood levels are achieved within an effective therapeuticrange for a longer duration than other conventional therapies, therebypreventing a rebound effect.

At least some compositions comprising the stimulant prodrugs of thepresent technology are resistant to abuse by parenteral routes ofadministration, such as intravenous “shooting,” intranasal “snorting,”or inhalation “smoking,” that are often employed during illicit use. Thepresent technology thus provides a stimulant based treatment modalityand dosage form for certain disorders requiring the stimulation of theCNS such as ADHD, ADD, obesity, narcolepsy, appetite suppressant,depression, anxiety, withdrawals, and wakefulness with reduced orprevented abuse potential. Although not wanting to be bound by anyparticular theory, it is believed that the treatment of such CNSconditions as noted above with compositions of the present technologyresults in substantially decreased abuse liability as compared toexisting stimulant treatment modalities and dosage forms.

At least some compositions comprising the stimulant prodrugs of thepresent technology can also be used for treating stimulant (cocaine,methamphetamine) abuse and addiction, for improving battle fieldalertness, and/or for combating fatigue.

In a first aspect, the presently described technology provides acomposition for stimulating the central nervous system of a human oranimal, comprising at least one stimulant chemically attached to a polarhydrophilic ligand, a salt thereof, a derivative thereof, or acombination thereof.

Preferably, the polar hydrophilic ligand prior to chemical attachment tothe at least one stimulant comprises one or more functional groupsconsisting essentially of hydroxyl, carboxylic acid, primary amine,secondary amine, ketone, aldehyde, acetyl halide, phosphate, phosphono,sulfate, sulfonyl, sulfonamide, or thiol. For example, the polarhydrophilic ligand can be a non-standard amino acid, a synthetic aminoacid, an amino acid derivative, an amino acid precursor, an aminoalcohol, or a mixture thereof. For another example, the polarhydrophilic ligand can be from some natural substrates or otherhydrophilic groups.

The compositions of the present technology preferably have no or asubstantially decreased pharmacological activity when administeredthrough injection or intranasal routes of administration. However, theyremain orally bioavailable. Again, not wanting to be bound by anyparticular theory, the bioavailability can be a result of the hydrolysisof the chemical linkage (e.g., a covalent linkage) following oraladministration. Hydrolysis of the chemical linkage is time-dependent,thereby allowing amphetamine or another stimulant to become available inits active form over an extended period of time. In at least oneembodiment, release of amphetamine or another stimulant is diminished oreliminated when the composition of the present technology is deliveredby parenteral routes.

For example, in one embodiment, the composition of the presenttechnology maintains its effectiveness and abuse resistance followingthe crushing of the tablet, capsule or other oral dosage form. Incontrast, conventional extended release formulations used to control therelease of amphetamine, for example, through incorporation into matricesare subject to release of up to the entire amphetamine content/doseimmediately following crushing. When the content of the crushed tabletis injected or snorted, the large dose of amphetamine produces the“rush” effect sought by addicts.

Examples of stimulants that can be chemically attached to the polarhydrophilic ligands of the present technology include amphetamine,adrafinil, modafinil, a minorex, benzylpiperazine, cathinone,chlorphentermine, chlobenzorex, cyclopentamine, diethylpropion,ephedrine, fenfluramine, 4-methyl-aminorex, methylone, methylphenidate,pemoline, phentermine, phenylephrine, propylhexadrine, pseudoephedrine,synephrine, metabolites thereof, derivatives thereof, and combinationsthereof. In some embodiments of the present technology, the at least onestimulant is amphetamine, a metabolite thereof, a derivative thereof, ora mixture thereof. Amphetamine can be in the form of dextro- (d-), levo-(l-), or racemic. One preferred amphetamine is d-amphetamine, whichpreferably is attached to a non-standard amino acid with a knowntoxicity profile. In addition, d-amphetamine could be preferablyattached to, for example, l-carnitine, l-lysinol, or choline.

In another aspect, the presently described technology provides a methodfor treating a human or animal patient with a disorder or conditionrequiring the stimulation of the patient's CNS (Central Nervous System),comprising the step of orally administering to the patient in need acomposition formulated for oral dosage comprising at least onenon-standard amino acid conjugate of amphetamine of the presenttechnology, wherein the blood levels of amphetamine in the patient'sbody are not unnecessarily elevated (i.e., blood level spikes) thuspreventing additional cardiovascular stress through, for example,increased blood pressure and/or heart rate.

In another aspect, the presently described technology provides a methodfor treating a human or animal patient with a disorder or conditionrequiring the stimulation of the patient's CNS, comprising orallyadministering to the patient in need a composition formulated for oraldosage comprising a pharmaceutically effective amount of at least onestimulant chemically attached to a polar hydrophilic ligand, a saltthereof, a derivative thereof, or a combination thereof. Preferably,after oral administration in accordance with the present technology, theblood levels of the stimulant such as amphetamine in the patient's bodycan maintain a therapeutically effect level, but do not result in aneuphoric effect (such as that observed with abuse of amphetamines orother stimulants).

In at least one embodiment of the present technology, the chemicalattachment (preferably covalent attachment) of the polar hydrophilicligand to the stimulant in the composition can substantially decreasethe potential for overdose when the composition is administered to thepatient by decreasing the toxicity of the stimulant at doses above thoseconsidered therapeutic, while maintaining the active agent/ingredient'spharmaceutical activity within a normal dose range. Without being boundby any particular theory, it is believed that the polar hydrophilicmoiety conjugated with amphetamine or another stimulant may decrease oreliminate the pharmacological activity of the stimulant. Therefore,restoring activity requires release of the stimulant from the polarhydrophilic ligand conjugate.

In a further aspect, the presently described technology provides amethod for delivering amphetamine, comprising providing a human oranimal patient with a therapeutically effective amount of at least onepolar hydrophilic conjugate of amphetamine, which can provide atherapeutically bioequivalent area under the curve (AUC) when comparedto free amphetamine, but does not provide a concentration max (C_(max))which results in an increased heart rate, increased blood pressure ordrug related euphoria when taken orally.

Other objects, advantages and embodiments of the invention are describedbelow and will be obvious from this description and practice of theinvention.

BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 compares mean plasma concentrations released from rats orallyadministered l-homoarginine-d-amphetamine or l-lysine-d-amphetamine.

FIG. 2 compares the relative blood levels of d-amphetamine released froml-homoarginine-d-amphetamine and l-lysine-d-amphetamine.

FIGS. 3 and 4 illustrate the difference in blood levels obtained fromthe study results shown in FIG. 2.

FIG. 5 compares average plasma concentrations from four (4) oral studiesof rats administered l-homoarginine-d-amphetamine orl-lysine-d-amphetamine.

FIG. 6 compares mean plasma concentrations released from rats orallyadministered l-citrulline-d-amphetamine or l-lysine-d-amphetamine.

FIG. 7 compares the mean plasma concentrations of d-amphetamine releasedfrom rats orally administered l-homocitrulline-d-amphetamine,l-homoarginine (NO₂)-d-amphetamine or l-lysine-d-amphetamine.

FIG. 8 compares the mean plasma concentrations of d-amphetamine releasedfrom rats intranasally administered l-homoarginine-d-amphetamine orl-lysine-d-amphetamine.

FIG. 9 compares the mean plasma concentrations of d-amphetamine releasedfrom rats intravenously administered d-amphetamine,l-homoargine-d-amphetamine or l-lysine-d-amphetamine.

DETAILED DESCRIPTION OF THE INVENTION

The presently described technology relates to novelprodrugs/compositions of stimulants, more specifically to stimulantschemically attached to polar hydrophilic ligands, salts thereof,derivatives thereof, or combinations thereof. Methods of making andusing the prodrugs/compositions of the present technology are alsodisclosed.

As used herein, a “non-standard” amino acid refers to a naturallyoccurring amino acid that is not one of the “standard” 20 amino acids.Non-standard amino acids do not have genetic codon, nor are theyincorporated into proteins of natural origin. One category ofnon-standard amino acids are metabolites of other amino acids.

As used herein, an “amino acid derivative” is a chemically modifiedversion of a naturally occurring amino acid (standard or non-standard).As used herein, an “amino acid precursor” refers to a molecule that caneither chemically or metabolically breakdown into a naturally occurringamino acid (standard or non-standard). As used herein, a “syntheticamino acid” is an amino acid that is not naturally occurring. As usedherein, an “amino alcohol” refers to a derivative of an amino acid(standard or non-standard, natural or synthetic) wherein the carboxylicacid group has been reduced to an alcohol.

As used herein, “amphetamine” shall mean any of the sympathomimeticphenethylamine derivatives which have central nervous system stimulantactivity, such as but not limited to, amphetamine(alpha-methyl-phenethylamine), methamphetamine, p-methoxyamphetamine,methylenedioxyamphetamine, 2,5-dimethoxy-4-methylamphetamine,2,4,5-trimethoxyamphetamine, and 3,4-methylenedioxy-methamphetamine.

As used herein, “in a manner inconsistent with the manufacturer'sinstructions” or similar expression is meant to include, but is notlimited to, consuming amounts greater than amounts described on thelabel or ordered by a licensed physician, and/or altering by any means(e.g., crushing, breaking, melting, separating etc.) the dosageformulation such that the composition maybe injected, inhaled or smoked.

As used herein, the phrases such as “decreased,” “reduced,” “diminished”or “lowered” is meant to include at least a 10% change inpharmacological activity with greater percentage changes being preferredfor reduction in abuse potential and overdose potential. For instance,the change may also be greater than 25%, 35%, 45%, 55%, 65%, 75%, 85%,95%, 96%, 97%, 98%, 99%, or increments therein.

Some abbreviations that may be used in the present application include:DCC=dicyclohexylcarbodiimide, NHS=N-hydroxysuccinimide, EtOAc=ethylacetate, MsOH=methanesulfonic acid,EDCI=1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide,PyBrOP=Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate,NMM=N-methylmorpholine or 4-methylmorpholine, TEA=triethylamine,CDI=Carbonyl diimidazole, IPAC=isopropyl acetate, DEA=diethylamine,BOP=(Benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate.

In accordance with some embodiments, the present technology providesstimulants such as amphetamine in a prodrug form. More specifically, thestimulant prodrug comprises at least one stimulant chemically attachedto a polar hydrophilic ligand, a salt thereof, a derivative thereof, ora combination thereof.

According to the presently described technology, polar hydrophilicmolecules or ligands can be chemically (preferably covalently) attachedto amphetamine (d-, l-, or racemic form or a mixture thereof) to producenovel polar, hydrophilic prodrugs of amphetamine. Other stimulants(including stimulant or stimulant-like drugs) can also be modified withthese ligands. Some examples of other stimulants include adrafinil,modafinil, a minorex, benzylpiperazine, cathinone, chlorphentermine,chlobenzorex, cyclopentamine, diethylpropion, ephedrine, fenfluramine,4-methyl-aminorex, methylone, methylphenidate, pemoline, phentermine,phenylephrine, propylhexadrine, pseudoephedrine, and Synephrine.Metabolites and derivatives of these and other stimulants could also bemodified with the same potential benefit. Examples of metabolites ofamphetamine include p-hydroxyamphetamine and p-hydroxyephedrine.

Please note that although the present technology sometimes may bedescribed with a reference to amphetamine only, amphetamine is merelyused as an example. It should be understood that any method orcomposition of the presently described technology is not limited toamphetamine.

In accordance with at least some embodiments, the polar hydrophilicligands suitable for the present technology contain at least one of thefollowing functional groups: hydroxyl, carboxylic acid, amine (primaryor secondary), ketone or aldehyde, acetyl halide, phosphate, phosphono,sulfate, sulfonyl, sulfonamide, and thiol. These functional groups canbe chemically attached to amphetamine, for example, through the primaryamine of amphetamine to form the following chemical linkages: carbamate,amide, urea, phosphonamide, phosphonamide, sulfonamide, or thiourea. Thefinal prodrug products of the present technology may be in a number ofderivative forms such as salt forms depending on other functionality ofthe attached ligands and any deprotection steps that may or may not benecessary.

Salts of the stimulant chemically attached to the polar hydrophilicligand that can be formed and utilized include, but are not limited to,mesylate, hydrochloride, sulfate, oxalate, triflate, citrate, malate,tartrate, phosphate, nitrate, benzoate, acetate, carbonate, hydroxide,sodium, potassium, magnesium, calcium, zinc, and ammonium salts.Further, in accordance with some embodiments, the salts may be requiredin multiple forms (e.g., di-, tri-, or tetra-). Other derivative formssuch as free base, free acid, or neutral forms may also be prepareddepending on the polar hydrophilic ligand used.

Polar hydrophilic ligands suitable for the presently describedtechnology can take a number of forms. These forms can be divided intoseveral categories including non-standard amino acids, amino acidderivatives, amino acid precursors, amino alcohols, synthetic amino acidderivatives, natural substrates, and other hydrophilic groups orligands. They can be in d-, l- or racemic form, or a mixture thereofalong with a number of other possible enantiomeric/diastereomeric formsdepending on the ligands. For example, the non-standard amino acid usedto produce the stimulant prodrug of the present technology can be eitherd- or l-form amino acid, racemic amino acid, or a mixture thereof.

Examples of non-standard amino acids suitable for the presentlydescribed technology include homoarginine, citrulline, homocitrulline,hydroxyproline, 2-hydroxy-4-(methylthio) butanoic acid (HMB),γ-aminobutyric acid, taurine, glutathione, statine, homocysteine,selenomethionine, and combinations thereof. Structures of somenon-standard amino acids are shown below.

Examples of amino acids derivatives or precursors suitable in thepresently described technology include isoserine, N-ω-nitro-arginine,N-ε,ε-dimethyl-lysine, buthionine, cysteic acid, ethionine, (2-aminoethyl) cysteine, cystathionine, 2-amino-3-ethyoxybutanoic acid,methylserine, ethoxytheorine, and combinations thereof.

Examples of synthetic amino acids suitable for use in the presentlydescribed technology include 2-amino-3-guanidinopropionic acid,2-amino-3-ureidopropioninc acid, 4-nitroanthranillic acid, andcombinations thereof. Structures of some synthetic amino acids for usein the practice of the present technology are provided below.

Examples of amino alcohols suitable for use in the presently describedtechnology include alaminol, indano, norephedrine, asparaginol,aspartimol, glutamol, leucinol, methioninol, phenylalaninol, prolinol,tryptophanol, valinol, isoleucinol, argininol, serinol, tyrosinol,threoninol, cysteinol, lysinol, histidinol, and combinations thereof.Structures of some amino alcohols for use in the practice of the presenttechnology are provided below.

Other polar hydrophilic ligands that can be used to produce stimulantprodrugs of the present technology include natural substrates, and otherhydrophilic groups.

As used herein, “natural substrates” refer to polar molecules that arereadily found in humans and can include essential or non-essentialnutrients and biological components. Other hydrophilic groups or ligandsinclude examples of compounds that occur in natural or are regarded asnon-toxic and could not be readily classified in the other groupings.

Examples of some natural substrates suitable for use in the presentlydescribed technology include carnitine, tartaric acid, biotin,pantothenic acid and salts, choline, cystine dimer, lactic acid, niacin,riboflavin, and combinations thereof. Structures of some preferrednatural substrates for use in the practice of the present technology areprovided below.

Examples of other hydrophilic groups suitable for use in the presentlydescribed technology include t-butylated hydroxyanisole (BHA), propionicacid, sorbic acid, erythorbic acid, methyl paraben, propyl gallate,propyl paraben, thiodipropionic acid, propylene glycol, pyridoxine,adipic acid, malic acid, acetoin, N-butyric acid, vanillin, geraniol,methyl anthranilate, benzoin, benzyl alcohol, and combinations thereof.Structures of two representative hydrophilic groups for use in thepractice of the present technology are provided below.

Generally, to produce a stimulant prodrug of the present technology, aselected polar hydrophilic ligand (e.g., a commercially availablenon-standard amino acid or amino acid derivative) can be added to thestimulant (e.g. amphetamine) in dextro, levo or racemic forms. Dependingon the polar hydrophilic ligand selected, one or more functional groupson the polar hydrophilic ligand may or may not need to be protectedprior to coupling the ligand with the stimulant.

For example, to conjugate an amino acid with amphetamine, the one ormore amino groups are preferably protected before the amino acid isreacted with amphetamine. Agents and methods for protecting amino groupsin a reactant are known in the art. Examples of protecting groups thatmay be used to protect the amino groups include, but are not limited to,fluorenylmethoxycarbonyl (Fmoc), t-butylcarbonate (Boc),trifluoroacetate (TFA), acetate (Ac) and benzyloxycarbonyl (Z). Aftercoupling with any standard coupling procedure, deprotection can occurwith a variety of strong acids to give the corresponding salt form. Saltforms may also be switched by first free basing the product and thenadding any acid. Neutral, free base or anionic salts may also be formed.Additional deprotection may be necessary in the case of some polarhydrophilic ligands such as homoarginine and any protected ureaderivative. These deprotections usually occur under hydrogenationconditions.

For another example, coupling of carnitine (d-, l-, or racemic) toamphetamine may require protection of the hydroxyl group prior tocoupling. In accordance with some embodiments, use of a silyl or benzoylgroup to protect the hydroxyl group would be preferred. Deprotection ofthe silyl can occur in water or slightly acidic media. On the otherhand, deprotection of benzoyl usually requires strong basic conditionssuch as in the presence of NaOMe.

More specifically, using a non-standard amino acid and amphetamine as anexample, the non-standard amino acid can be attached to amphetamine tomake an amino acid conjugate of amphetamine or salts thereof inaccordance with the presently described technology. Preferably, theamino acid is covalently attached to amphetamine through the C-terminusof the amino acid. The N-terminus or the side chain amino group of theamino acid may be in a free and unprotected state, or in the form of asalt thereof. Alternatively, in some embodiments, the amino acid can beattached to amphetamine through the N-terminus. Examples of salts ofamino acid conjugates of amphetamine that can be formed andadministrated to patients in accordance with the presently describedtechnology include, but are not limited to, mesylate, hydrochloride,sulfate, oxalate, triflate, citrate, malate, tartrate, phosphate,nitrate, and benzoate salts, and mixtures thereof.

To conjugate the amino acid with amphetamine, the one or more aminogroups are preferably protected using agents described above before theamino acid is reacted with amphetamine. The amino acid whose aminogroups are protected can be referred to as an N-protected amino acid.One can either protect the amino groups in situ during the productionprocess, or use commercially available N-protected amino acids directly.Preferably, the carboxylic acid group in the N-protected amino acid isactivated by an acid activating agent (sometimes also called couplingreagent) to help the reaction of the N-protected amino acid withamphetamine. General information about the reaction of amino acids toform peptide bonds can be found in, for example, G. C. Barett, D. T.Elmare, Amino Acids and Peptides, page 151-156, Cambridge UniversityPress, UK (1st edition, 1998); Jones, J., Amino Acid and PeptideSynthesis, pages 25-41, Oxford University Press, UK (2nd edition, 2002),which are incorporated herein by reference in their entirety.

One category of acid activating agents (coupling reagents) well known inthe art are carbodiimides. Examples of carbodiimide acid activatingagents include, but are not limited to, dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (EDCI), anddiisopropylcarbodiimide (DIPCDI). Examples of other coupling reagentsthat could be used include bromo-tris-pyrrolidinophosphoniumhexafluorophosphate,(benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphoniumhexafluorophosphate, PCl₅/PhH, SOCl₂, N₂H₄,1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, other phosphoniumreagents, and uronium reagents. The use of appropriate acyl halide oranhydride is also contemplated.

The N-protected amino acid conjugate of amphetamine resulting from thereaction of the N-protected amino acid and amphetamine as describedabove can then be de- or un-protected with a strong acid to produce thecorresponding final salt form of the amino acid conjugate ofamphetamine.

Scheme 1 below outlines an exemplary route for the synthesis of aderivative of amphetamine chemically attached to homoarginine inaccordance with the presently described technology. In this exemplaryreaction scheme, an HCl salt form of homoarginine-amphetamine isproduced. The procedure uses tert-butyloxycarbonyl (Boc) and nitroprotected homoarginine (Boc-homoarginine(Nitro)) as the startingmaterial. In this exemplary reaction scheme, coupling agent EDCI isadded to Boc-homoarginine. N-hydroxy succinamide (NHS) is then added tothe reaction mixture in dimethylformamide (DMF). A stable, yet stillactivated, succinic ester of Boc-homoarginine(nitro) is formed.Amphetamine is then added to the resulting succinic ester ofBoc-homoarginine(nitro) to make the corresponding protected prodrug,Boc-homoarginine(nitro)-Amp. This protected prodrug can be de- orun-protected using hydrogenation followed by a strong acid such asmethanesulfonic acid (MsOH) or hydrochloric acid to produce the prodrugof amphetamine, which is a hydrochloride salt ofhomoarginine-amphetamine in this exemplary reaction scheme.

Examples of other solvents that can be used in the presently describedtechnology include, but are not limited to, isopropyl acetate (IPAC),acetone, and dichloromethane (DCM), dimethylformamide (DMF), ethylacetate, chloroform, dimethyl sulfoxide, dioxane, diethyl ether, methylt-butyl ether, hexanes, heptane, methanol, ethanol, isopropanol, andbutanol. A mixture of different solvents can also be used. Co-bases suchas tertiary amines may or may not be added in the coupling reaction ofthe presently described technology. Examples of suitable co-basesinclude, but are not limited to, 1-methylmorpholine (NMM),4-methylmorpholine, triethylamine (TEA), ammonia or any tertiary aminebase.

The amphetamine to be chemically attached to polar hydrophilic ligandsof the presently described technology can be in d-form, l-form, orracemic form, or can be a mixture thereof. In accordance with someembodiments of the presently described technology, d-amphetamine(dextroamphetamine) and a non-standard amino acid with a known toxicityprofile are preferably used to make an amphetamine prodrug. Otherpreferred polar hydrophilic ligands to form d-amphetamine prodrugsinclude, for example, l-carnitine, l-lysinol, or choline. In accordancewith some other embodiments, the prodrugs of d-amphetamine can be usedin combination with a prodrug of l-amphetamine or l-amphetamine itself.

Scheme 2 below outlines an exemplary route for the synthesis of aderivative of amphetamine chemically attached to selenomethionine inaccordance with the presently described technology. The amphetamineprodrug produced here is in a sulfate salt form.

Scheme 3 below outlines an exemplary route for the synthesis of aderivative of amphetamine chemically attached to statine in accordancewith the presently described technology. The amphetamine prodrugproduced here is in an HCl salt form.

Scheme 4 below outlines an exemplary route for the synthesis of aderivative of amphetamine chemically attached to isoserine in accordancewith the presently described technology. The amphetamine prodrugproduced here is in an MsOH salt form.

Scheme 5 below outlines an exemplary route for the synthesis of aderivative of amphetamine chemically attached to cystathionine inaccordance with the presently described technology. The amphetamineprodrug produced here is in an HCl salt form.

Scheme 6 below outlines an exemplary route for the synthesis of aderivative of amphetamine chemically attached to ethoxytheorine inaccordance with the presently described technology. The amphetamineprodrug produced here is in an HCl salt form.

Scheme 7 below outlines an exemplary route for the synthesis of aderivative of amphetamine chemically attached to2-amino-3-guanidinopropionic acid in accordance with the presentlydescribed technology. The amphetamine prodrug produced here is in anMsOH salt form.

Scheme 8 below outlines an exemplary route for the synthesis of aderivative of amphetamine chemically attached to lysinol-carbamate inaccordance with the presently described technology. The amphetamineprodrug produced here is in an HCl salt form.

Scheme 9 above outlines an exemplary route for the synthesis of aderivative of amphetamine chemically attached to lysinol-urea inaccordance with the presently described technology.

Scheme 10 below outlines an exemplary route for the synthesis of aderivative of amphetamine chemically attached to carnitine in accordancewith the presently described technology.

Scheme 11 below outlines an exemplary route for the synthesis of aderivative of amphetamine chemically attached to choline in accordancewith the presently described technology.

At least some polar, hydrophilic stimulant prodrugs of the presenttechnology have no or a substantially decreased pharmacological activitywhen administered through injection or intranasal routes ofadministration. However, they remain orally bioavailable. Thebioavailability can be a result of the hydrolysis of the covalentlinkage following oral administration. Hydrolysis of a chemical linkageis time-dependent, thereby allowing amphetamine and other metabolitessuch as p-hydroxyamphetamine and p-hydroxyephedrine or another stimulantto become available in its active form over an extended period of time.Therefore, the prodrug compounds of the present technology can releaseamphetamine or another stimulant over an extended period and provide atherapeutically area under the curve (AUC) when compared to freeamphetamine or another stimulant, with little or no spike inconcentration max (C_(max)) or equivalent C_(max). Not wanting to bebound by any particular theory, it is believed that since non-standardamino acids and the other suitable polar hydrophilic ligands are used toproduce the prodrugs, the in vivo breakdown of the prodrugs by enzymeswould occur at a slower rate than, for example, when a standard aminoacid is used to conjugate the stimulants. This will allow the prodrugsto release amphetamine or other stimulants slowly and, preferably, onlyunder in vivo conditions.

As a person of ordinary skill in the art will understand, drug productsare considered pharmaceutical equivalents if they contain the sameactive ingredient(s), are of the same dosage form, route ofadministration and are identical in strength or concentration.Pharmaceutically equivalent drug products are formulated to contain thesame amount of active ingredient in the same dosage form and to meet thesame or compendial or other applicable standards (i.e., strength,quality, purity, and identity), but they may differ in characteristicssuch as shape, scoring configuration, release mechanisms, packaging,excipients (including colors, flavors, preservatives), expiration time,and, with certain limits, labeling. Drug products are considered to betherapeutic equivalents only if they are pharmaceutical equivalents andif they can be expected to have the same clinical effect and safetyprofile when administered to patients under the conditions specified inthe labeling. The term “bioequivalent,” on the other hand, describespharmaceutical equivalent or pharmaceutical alternative products thatdisplay comparable bioavailability when studied under similarexperimental conditions.

Standard amino acids such as lysine or glutamic acid are notcontemplated for the presently described technology. Because standardamino acids are essential parts of all dietary requirements, it would beexpected that the prodrug of the present technology conjugated with astandard amino acid would be released at a faster rate. By usingnon-standard amino acids, synthetic amino acids, amino acid derivativesor precursors, or other polar hydrophilic ligands of the presentlydescribed technology, the release rate of amphetamine or anotherstimulant will be reduced due to the difference in overall digestionrate of the stimulant prodrug.

Once produced, the prodrug of amphetamine (or another stimulant) of thepresent technology can be administered through oral routes of deliveryand once administered will release the stimulant under digestiveconditions. Due to the hydrophilic and polar nature of the prodrug andthe slow rate of hydrolysis of the chemical linkage as described above,should high levels of drug be administered either accidentally orintentionally, the prodrug will be cleared by metabolic and/or excretorypathways prior to releasing large amounts of the stimulant. Also,release of amphetamine (or another stimulant) over an extended periodshould alleviate or diminish drug induced side-effects that can limit orterminate amphetamine therapy. These side effects include increase inthe heart and respiration rates, increased blood pressure, dilation ofthe pupils of the eyes, and decreased appetite. Other side effectsinclude anxiety, blurred vision, sleeplessness, and dizziness. Also,amphetamines and other stimulants are power psychostimulants and areprone to substance abuse.

Substance abuse of stimulants is often characterized by an escalation ofevents. First, a substantial “rush” or high may be obtained fromincreasing oral dosages. Due to the properties of these polar,hydrophilic prodrugs, these potential routes for abuse can be mitigatedvia the polar nature of the prodrug. That is, once administered athigher than therapeutic levels, the body will excrete any remainingprodrug without breakdown into amphetamine. After oral amounts exceed anattainable amount, other routes can be explored including smoking,snorting, or injection. In accordance with the presently describedtechnology, release of amphetamine or another stimulant would only occurunder desired physiological conditions. Preferably, other routes ofadministration (e.g., intranasal or intravenous) do not break theprodrug down to any appreciable extent. Also preferably, external means(chemical, enzymatic or other) will not break the prodrug down to anyappreciable extent either. The breakdown ratio of the prodrug that canbe achieved through external means is preferably less than about 50%,alternatively less than about 25%, alternatively less than about 20%,alternatively less than about 10%.

The presently described technology utilizes covalent modification ofamphetamine by a non-standard amino acid, an amino acid derivative orany polar hydrophilic group to decrease its potential for causingbehavioral deterioration or the rebound effect. It is believed thatsince the amphetamine is covalently modified to form the polarhydrophilic conjugate of the present technology and releases slowly overthe entire length of the day, little or no rebound effect can occur dueto the slow continuous release of the active ingredient/drug/therapeuticcomponent.

Compounds, compositions and methods of the presently describedtechnology are also believed to provide reduced potential for rebound,reduced potential for abuse or addiction, and/or improve amphetamine'sstimulant related toxicities. By limiting the blood level spike, dosesare kept at levels required for a clinically significant effect withoutthe unnecessary levels administered with other therapies. It is widelyheld that these spikes in blood levels can lead to cardiovasculartoxicity in the form of higher blood pressure and rapid heart rate inaddition to the euphoria encountered in drug abuse. Also, with a fullday therapy, the risk of re-dosing is lowered, thus preventingadditional toxicities or drug abuse issues.

The polar, hydrophilic prodrugs of stimulants of the presently describedtechnology could be used for any condition requiring the stimulation ofthe central nervous system (CNS). These conditions include, for example,attention deficit hyperactivity disorder (ADHD), attention deficitdisorder (ADD), obesity, narcolepsy, appetite suppressant, depression,anxiety, withdrawals (e.g., alcohol withdrawals or drug withdrawals),and wakefulness. Some stimulants such as amphetamine have alsodemonstrated usefulness in treating stimulant (e.g., cocaine,methamphetamine) abuse and addiction. Amphetamine stimulants have alsobeen used extensively to improve battle field alertness and to combatfatigue.

Therefore, in accordance with some embodiments, the presently describedtechnology provides stimulant compositions comprising at least onepolar, hydrophilic stimulant prodrug of the present technology.

One embodiment is a composition that can prevent behavioraldeterioration of amphetamine dosing comprising at least one polarhydrophilic conjugate of amphetamine.

Another embodiment is a composition for safely delivering a stimulant,comprising a therapeutically effective amount of at least one polar,hydrophilic prodrug of the stimulant of the present technology whereinthe polar hydrophilic moiety can reduce the rate of absorption of thestimulant as compared to delivering the unconjugated stimulant or thestimulant conjugated to a standard amino acid, for example.

Another embodiment of the present technology is a composition that canreduce amphetamine toxicity, comprising at least one polar hydrophilicprodrug of amphetamine wherein the non-standard amino acid moiety canrelease amphetamine over the entire course of a day providing a limitedbehavioral deterioration effect.

Another embodiment of the present technology is a composition that canreduce amphetamine toxicity, comprising at least one polar, hydrophilicprodrug of amphetamine of the present technology wherein the polarhydrophilic moiety can provide a serum release curve which does notincrease above amphetamine's toxicity level when given at dosesexceeding those within the therapeutic range of amphetamine.

Another embodiment of the present technology is a composition that canreduce bioavailability of amphetamine, comprising at least one polar,hydrophilic prodrug of amphetamine of the present technology wherein theamphetamine prodrug can maintain a steady-state serum release curvewhich can provide a therapeutically effective bioavailability butprevent spiking or increased blood serum concentrations compared tounconjugated amphetamine or amphetamine conjugated with a standard aminoacid when given at doses exceeding those within the therapeutic range ofamphetamine.

Another embodiment of the present technology is a composition comprisingat least one polar, hydrophilic prodrug of amphetamine of the presenttechnology that can prevent a C_(max) or equivalent C_(max) spike foramphetamine when taken by means other than orally while still providinga therapeutically effective bioavailability curve if taken orally.

Another embodiment of the present technology is a composition that canprevent a toxic release profile in a patient comprising at least onepolar, hydrophilic prodrug of amphetamine of the present technologywherein the amphetamine prodrug can maintain a steady-state serumrelease curve which provides a therapeutically effective bioavailabilitybut prevents spiking or increased blood serum concentrations compared tounconjugated amphetamine or amphetamine conjugated with a naturallyoccurring and standard amino acid.

One or more embodiments of the present technology provide stimulant suchas amphetamine compositions which allow the stimulant to betherapeutically effective when delivered at the proper dosage butreduces the rate of absorption or extent of bioavailability of thestimulant when given at doses exceeding those within the therapeuticrange of the stimulant. One or more embodiments of the presenttechnology also provide stimulant compositions wherein the polarhydrophilic moiety increases the rate of clearance of the stimulant whengiven at doses exceeding those within the therapeutic range of thestimulant.

In one or more embodiments, the stimulant compositions of the presenttechnology have substantially lower toxicity compared to unconjugatedstimulant or the stimulant conjugated with a standard amino acid. In oneor more embodiments, the stimulant compositions of the presenttechnology can reduce or eliminate the possibility of overdose by oraladministration. In one or more embodiments, the stimulant compositionsof the present technology can reduce or eliminate the possibility ofoverdose by intranasal administration. In one or more embodiments, thestimulant compositions of the present technology can reduce or eliminatethe possibility of overdose by injection. In one or more embodiments,the stimulant compositions of the present technology can reduce oreliminate the possibility of overdose by inhalation.

In one or more embodiments, the polar, hydrophilic prodrugs ofstimulants of the present technology may further comprise a polymerblend which comprises a hydrophilic polymer and/or a water-insolublepolymer. The polymers may be used according to industry standards tofurther enhance the sustained release/abuse resistant properties of thestimulant prodrug of the present technology without reducing the abuseresistance. For instance, a composition might include: about 70% toabout 100% stimulant prodrug of the present technology by weight, fromabout 0.01% to about 10% of a hydrophilic polymer (e.g. hydroxypropylmethylcellulose), from about 0.01% to about 2.5% of a water-insolublepolymer (e.g. acrylic resin), from about 0.01% to about 1.5% ofadditives (e.g. magnesium stearate), and from about 0.01% to about 1%colorant by weight.

Hydrophilic polymers suitable for use in the sustained releaseformulations include one or more natural or partially or totallysynthetic hydrophilic gums such as acacia, gum tragacanth, locust beangum, guar gum, or karaya gum, modified cellulosic substances such asmethylcellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose,hydroxypropyl cellulose, hydroxyethylcellulose, carboxymethylcellulose;proteinaceous substances such as agar, pectin, carrageen, and alginates;and other hydrophilic polymers such as carboxypolymethylene, gelatin,casein, zein, bentonite, magnesium aluminum silicate, polysaccharides,modified starch derivatives, and other hydrophilic polymers known tothose of skill in the art, or a combination of such polymers. Thesehydrophilic polymers gel and would dissolve slowly in aqueous acidicmedia thereby allowing the stimulant prodrug to diffuse from the gel inthe stomach. When the gel reaches the intestines it would dissolve incontrolled quantities in the higher pH medium to allow further sustainedrelease. Preferred hydrophilic polymers are the hydroxypropylmethylcelluloses such as those manufactured by The Dow Chemical Companyand known as Methocel ethers, such as Methocel E1OM.

Other formulations according to one or more embodiments of the presenttechnology may further comprise pharmaceutical additives including, butnot limited to, lubricants such as magnesium stearate, calcium stearate,zinc stearate, powdered stearic acid, hydrogenated vegetable oils, talc,polyethylene glycol, and mineral oil; colorants such as Emerald GreenLake, FD&C Red No. 40, FD&C Yellow No. 6, D&C Yellow No. 10, or FD&CBlue No. 1 and other various certified color additives (See 21 CFR, Part74); binders such as sucrose, lactose, gelatin, starch paste, acacia,tragacanth, povidone, polyethylene glycol, Pullulan and corn syrup;glidants such as colloidal silicon dioxide and talc; surface activeagents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate,triethanolamine, polyoxyethylene sorbitan, poloxalkol, and quaternaryammonium salts; preservatives and stabilizers; excipients such aslactose, mannitol, glucose, fructose, xylose, galactose, sucrose,maltose, xylitol, sorbitol, chloride, sulfate and phosphate salts ofpotassium, sodium, and magnesium; and/or any other pharmaceuticaladditives known to those of skill in the art. In one preferredembodiment, a sustained release formulation of the present technologyfurther comprises magnesium stearate and Emerald Green Lake.

The stimulant compositions of the present technology, which comprises atleast one polar, hydrophilic stimulant prodrug of the presenttechnology, can be further formulated with excipients, and may bemanufactured according to any appropriate method known to those of skillin the art of pharmaceutical manufacture. For instance, the stimulantprodrug and a hydrophilic polymer may be mixed in a mixer with analiquot of water to form a wet granulation. The granulation may be driedto obtain hydrophilic polymer encapsulated granules of the stimulantprodrug. The resulting granulation may be milled, screened, then blendedwith various pharmaceutical additives such as, for example, waterinsoluble polymers, and/or additional hydrophilic polymers. Theformulation may then be tableted and may further be film coated with aprotective coating which rapidly dissolves or disperses in gastricjuices.

It should be noted that the above additives are not required for thestimulant composition of the present technology to have sustainedrelease and abuse resistance properties. The stimulant prodrug of thepresent technology itself can control the release of the stimulant intothe digestive tract over an extended period of time resulting in animproved profile when compared to immediate release combinations andprevention of abuse without the addition of the above additives. In oneor more embodiments of the present technology, no further sustainedrelease additives are required to achieve a blunted or reducedpharmacokinetic curve (e.g., reduced euphoric effect) while achievingtherapeutically effective amounts of stimulant release when takenorally.

The compounds and compositions of the presently described technology canbe formulated into and administered by a variety of dosage forms,preferably, through any oral routes of delivery. Once administered, theprodrugs will release amphetamine or another stimulant under digestiveconditions. Any biologically-acceptable dosage form known to persons ofordinary skill in the art, now or in the future, and combinationsthereof, are contemplated for use with the present technology. Examplesof preferred dosage forms include, without limitation, chewable tablets,quick dissolve tablets, effervescent tablets, reconstitutable powders,elixirs, liquids, solutions, suspensions, emulsions, tablets,multi-layer tablets, bi-layer tablets, capsules, soft gelatin capsules,hard gelatin capsules, caplets, troches, lozenges, chewable lozenges,beads, powders, granules, particles, microparticles, dispersiblegranules, cachets, thin strips, oral films, transdermal patches, andcombinations thereof. Preferred dosage forms include, but are notlimited to, capsules, thin strips, and solution formulations.

Formulations of the present technology suitable for oral administrationcan be presented as discrete units, such as capsules, caplets ortablets. These oral formulations also can comprise a solution or asuspension in an aqueous liquid or a non-aqueous liquid. The formulationcan be an emulsion, such as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The oils can be administered by adding thepurified and sterilized liquids to a prepared enteral formula, which canthen be placed in the feeding tube of a patient who is unable toswallow.

If the capsule form is chosen, for example, excipients used in thecapsule formulation could be broken up into four separate groups: bulkagent/binder, disintergrant, lubricant and carrier. A preferred capsuleformulation comprises from about 50% to about 90% by weight of a bulkagent such as various types of microcrystalline cellulose, from about 1%to about 5% by weight of a disintegrant such as croscarmellose sodium,from about 0.5% to about 2.5% of a lubricant such as magnesium stearateor other fatty acid salts. The carrier can be either hard gelatincapsules, and preferably use the smaller sized ones such as #3 or #4hard gelatin capsules.

Soft gel or soft gelatin capsules may be prepared, for example, bydispersing the formulation of the present technology in an appropriatevehicle (vegetable oils are commonly used) to form a high viscositymixture. This mixture can then be encapsulated with a gelatin based filmusing technology and machinery known to those in the soft gel industry.The individual units so formed are then dried to constant weight.

Chewable tablets, for example, may be prepared by mixing theformulations of the present technology with excipients designed to forma relatively soft, flavored, tablet dosage form that is intended to bechewed rather than swallowed. Conventional tablet machinery andprocedures, that is both direct compression and granulation, i.e., orslugging, before compression, can be utilized. Those individualsinvolved in pharmaceutical solid dosage form production are versed inthe processes and the machinery used as the chewable dosage form is avery common dosage form in the pharmaceutical industry.

Film-coated tablets, for example, may be prepared by coating tabletsusing techniques such as rotating pan coating methods or air suspensionmethods to deposit a contiguous film layer on a tablet.

Compressed tablets, for example, may be prepared by mixing theformulation of the present technology with excipients intended to addbinding qualities to disintegration qualities. The mixture can be eitherdirectly compressed or granulated then compressed using methods andmachinery known to those in the industry. The resultant compressedtablet dosage units are then packaged according to market need, i.e.,unit dose, rolls, bulk bottles, blister packs, etc.

One preferred formulation of the polar hydrophilic prodrugs is a fastdissolving oral film or thin strip. Methods and other ingredients neededto make oral films or thin strips are known in the art. Potential filmforming agents include pullulan, hydroxypropylmethyl cellulose,hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol,sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guargum, acacia gum, Arabic gum, polyacrylic acid, amylase, starch, dextrin,pectin, chitin, chitosin, levan, elsinan, collagen, gelatin, zein,gluten, soy protein isolate, whey protein isolate, casein, and mixturesthereof.

Also, saliva stimulating agents, plasticizing agents, cooling agents,surfactants, emulsifying agents, thickening agents, binding agents,sweeteners, flavoring, coloring agents, preservatives, or taste maskingresins may be employed in the oral films or thin strips. Preferredagents include: pullulan, triethanol amine stearate, methyl cellulose,starch, triacetin, polysorbate 80, xanthan gum, maltitol, sorbitol andglycerol.

The presently described technology also contemplates the use ofbiologically-acceptable carriers which may be prepared from a wide rangeof materials. Without being limited thereto, such materials includediluents, binders and adhesives, lubricants, plasticizers,disintegrants, colorants, bulking substances, flavorings, sweeteners andmiscellaneous materials such as buffers and adsorbents in order toprepare a particular medicated composition.

Binders may be selected from a wide range of materials such ashydroxypropylmethylcellulose, ethylcellulose, or other suitablecellulose derivatives, povidone, acrylic and methacrylic acidco-polymers, pharmaceutical glaze, gums, milk derivatives, such as whey,starches, and derivatives, as well as other conventional binders knownto persons skilled in the art. Exemplary non-limiting solvents arewater, ethanol, isopropyl alcohol, methylene chloride or mixtures andcombinations thereof. Exemplary non-limiting bulking substances includesugar, lactose, gelatin, starch, and silicon dioxide.

Preferred plasticizers may be selected from the group consisting ofdiethyl phthalate, diethyl sebacate, triethyl citrate, cronotic acid,propylene glycol, butyl phthalate, dibutyl sebacate, castor oil andmixtures thereof, without limitation. As is evident, the plasticizersmay be hydrophobic as well as hydrophilic in nature. Water-insolublehydrophobic substances, such as diethyl phthalate, diethyl sebacate andcastor oil are used to delay the release of water-soluble vitamins, suchas vitamin B6 and vitamin C. In contrast, hydrophilic plasticizers areused when water-insoluble vitamins are employed which aid in dissolvingthe encapsulated film, making channels in the surface, which aid innutritional composition release.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of the present technology can includeother suitable agents such as flavoring agents, preservatives andantioxidants. Such antioxidants would be food acceptable and couldinclude, for example, vitamin E, carotene, BHT or other antioxidantsknown to those of skill in the art.

Other compounds which may be included are, for example, medically inertingredients, e.g., solid and liquid diluent, such as lactose, dextrose,saccharose, cellulose, starch or calcium phosphate for tablets orcapsules, olive oil or ethyl oleate for soft capsules and water orvegetable oil for suspensions or emulsions; lubricating agents such as,talc, stearic acid, magnesium or calcium stearate and/or polyethyleneglycols; gelling agents such as colloidal clays; thickening agents suchas gum tragacanth or sodium alginate, binding agents such as starches,arabic gums, gelatin, methylcellulose, carboxymethylcellulose orpolyvinylpyrrolidone; disintegrating agents such as starch, alginicacid, alginates or sodium starch glycolate; effervescing mixtures;dyestuff; sweeteners; wetting agents such as lecithin, polysorbates orlaurylsulphates; and other therapeutically acceptable accessoryingredients, such as humectants, preservatives, buffers andantioxidants, which are known additives for such formulations.

For oral administration, fine powders or granules containing diluting,dispersing and/or surface-active agents may be presented in a draught,in water or a syrup, in capsules or sachets in the dry state, in anon-aqueous suspension wherein suspending agents may be included, or ina suspension in water or a syrup. Where desirable or necessary,flavoring, preserving, suspending, thickening or emulsifying agents canbe included.

Liquid dispersions for oral administration may be syrups, emulsions orsuspensions. The syrups may contain as a carrier, for example,saccharose or saccharose with glycerol and/or mannitol and/or sorbitol.The suspensions and the emulsions may contain a carrier, for example anatural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose or polyvinyl alcohol.

The dose range for adult or pediatric human beings will depend on anumber of factors including the age, weight and condition of thepatient. Suitable oral dosages of the prodrugs of one stimulant of thepresently described technology can be the equivalents of those typicallyfound in treatments using that stimulant. For example, typical dosagesfor amphetamine salts can range from about 1 mg to about 100 mg,although higher dosages may be approved at later dates. Using themolecular weight of the prodrug of the present technology, the releasepercentage (% release) of amphetamine from the prodrug and desireddosage forms of the required amphetamine, the following equation can begenerated:

grams of a prodrug needed=(dosage/molecular weight of amphetamine)(%release)(molecular weight of the prodrug)

Tablets, capsules, and other forms of presentation provided in discreteunits conveniently contain a daily dose, or an appropriate fractionthereof, of one or more of the prodrug compounds of the invention. Forexample, the units may contain from about 1 mg to about 1000 mg,alternatively from about 5 mg to about 500 mg, alternatively from about5 mg to about 250 mg, alternatively from about 10 mg to about 100 mg ofone or more of the prodrug compounds of the presently describedtechnology.

It is also possible for the dosage form of the present technology tocombine any forms of release known to persons of ordinary skill in theart. These conventional release forms include immediate release,extended release, pulse release, variable release, controlled release,timed release, sustained release, delayed release, long acting, andcombinations thereof. The ability to obtain immediate release, extendedrelease, pulse release, variable release, controlled release, timedrelease, sustained release, delayed release, long acting characteristicsand combinations thereof is known in the art.

Compositions of the present technology may be administered in a partial,i.e., fractional dose, one or more times during a 24 hour period, asingle dose during a 24 hour period of time, a double dose during a 24hour period of time, or more than a double dose during a 24 hour periodof time. Fractional, double or other multiple doses may be takensimultaneously or at different times during the 24 hour period. Thedoses may be uneven doses with regard to one another or with regard tothe individual components at different administration times.

Likewise, the compositions of the present technology may be provided ina blister pack or other such pharmaceutical package. Further, thecompositions of the present technology may further include or beaccompanied by indicia allowing individuals to identify the compositionsas products for a prescribed treatment. The indicia may additionallyinclude an indication of the above specified time periods foradministering the compositions. For example, the indicia may be timeindicia indicating a specific or general time of day for administrationof the composition, or the indicia may be a day indicia indicating a dayof the week for administration of the composition. The blister pack orother combination package may also include a second pharmaceuticalproduct.

It will be appreciated that the pharmacological activity of thecompositions of the present technology can be demonstrated usingstandard pharmacological models that are known in the art. Furthermore,it will be appreciated that the compositions of the present technologycan be incorporated or encapsulated in a suitable polymer matrix ormembrane for site-specific delivery, or can be functionalized withspecific targeting agents capable of effecting site specific delivery.These techniques, as well as other drug delivery techniques, are wellknown in the art.

In one or more embodiments of the present technology, the solubility anddissolution rate of the composition can be substantially changed underdifferent physiological conditions encountered, for example, in theintestine, at mucosal surfaces, or in the bloodstream. In one or moreembodiments of the present technology, the solubility and dissolutionrate of the composition can substantially decrease the bioavailabilityof the amphetamine, particularly at doses above those intended fortherapy. In one embodiment of the present technology, the decrease inbioavailability occurs upon intranasal administration. In anotherembodiment, the decrease in bioavailability occurs upon intravenousadministration.

For each of the described embodiments of the present technology, one ormore of the following characteristics can be realized: Thecardiovascular toxicity of the amphetamine prodrug is substantiallylower than that of the unconjugated amphetamine and amphetamineconjugated with a standard amino acid. The covalently bound polarhydrophilic moiety reduces or eliminates the possibility of behavioraldeterioration or the rebound effect. The covalently bound polarhydrophilic moiety reduces or eliminates the possibility of abuse byintranasal administration. The covalently bound polar hydrophilic moietyreduces the possibility of abuse by injection.

The presently described technology further provides methods for alteringand/or delivering amphetamines and other stimulants in a manner that candecrease their potential for abuse. Methods of the present technologyprovide various ways to regulate pharmaceutical dosage throughconjugating stimulants such as amphetamine with polar hydrophilicligands of the present technology.

One embodiment provides a method for preventing behavioral deteriorationor the rebound effect by administering to a patient in need anamphetamine prodrug composition of the present technology, whichcomprises at least one polar hydrophilic conjugate of amphetamine.

Another embodiment provides a method for safely delivering amphetamineor another stimulant comprising providing a therapeutically effectiveamount of at least one polar, hydrophilic prodrug of stimulant of thepresent technology wherein the polar hydrophilic moiety can reduce therate of absorption of amphetamine or another stimulant as compared todelivering the unconjugated stimulant or the stimulant conjugated with astandard amino acid, for example.

Another embodiment provides a method for reducing stimulant toxicitycomprising providing a patient with at least one polar, hydrophilicprodrug of the stimulant of the present technology, wherein the polarhydrophilic moiety can increase the rate of clearance ofpharmacologically active stimulant (i.e., released stimulant such asamphetamine) when given at doses exceeding those within the therapeuticrange of the stimulant.

Another embodiment provides a method for reducing stimulant toxicitycomprising providing a patient with at least one polar, hydrophilicstimulant prodrug of the present technology, wherein the polarhydrophilic moiety can provide a serum release curve which does notincrease above the stimulant's toxicity level when given at dosesexceeding those within the therapeutic range for the unconjugatedstimulant.

Another embodiment provides a method for reducing bioavailability ofstimulant a comprising providing at least one polar, hydrophilicstimulant prodrug of the present technology, wherein the stimulantprodrug can maintain a steady-state serum release curve which provides atherapeutically effective bioavailability but prevents spiking orincreased blood serum concentrations compared to unconjugated stimulantwhen given at doses exceeding those within the therapeutic range for theunconjugated stimulant or the stimulant conjugated with a standarddiamino acid, for example.

Another embodiment provides a method for preventing a C_(max) orequivalent C_(max) spike for amphetamine or another stimulant whilestill providing a therapeutically effective bioavailability curvecomprising the step of administering to a patient at least one polar,hydrophilic prodrug of amphetamine or another stimulant of the presenttechnology.

Another embodiment provides a method for preventing a toxic releaseprofile in a patient comprising administering to a patient at least onepolar, hydrophilic stimulant prodrug of the present technology, whereinthe stimulant prodrug can maintain a steady-state serum release curvewhich provides a therapeutically effective bioavailability but preventsspiking or increased blood serum concentrations compared to unconjugatedstimulant or the stimulant conjugated to a standard amino acid,particularly when taken at doses above prescribed amounts.

Another embodiment of the present technology is a method for reducing orpreventing abuse of a stimulant comprising providing, administering, orprescribing a composition to a patient in need thereof, wherein saidcomposition comprises at least one polar, hydrophilic stimulant prodrugof the present technology such that the pharmacological activity of thestimulant is decreased when the composition is used in a mannerinconsistent with the manufacturer's instructions.

Another embodiment of the present technology is a method for reducing orpreventing abuse of a stimulant such as amphetamine comprising consumingat least one polar, hydrophilic prodrug of the stimulant of the presenttechnology, wherein said prodrug comprises the stimulant covalentlyattached to a polar hydrophilic ligand such that the pharmacologicalactivity of the stimulant is substantially decreased when thecomposition is used in a manner inconsistent with the manufacturer'sinstructions.

Another embodiment of the present technology is a method of preventingbehavioral deterioration or the rebound effect of amphetamine orstimulant treatment comprising providing, administering, or prescribingan amphetamine composition of the presently described technology to apatient in need thereof, wherein said composition comprises at least onepolar hydrophilic prodrug of amphetamine that can decrease the potentialof behavioral deterioration or the rebound effect from amphetamine orstimulant treatment.

Another embodiment of the present technology is a method for reducing orpreventing the euphoric effect of a stimulant comprising providing,administering, or prescribing to a human or animal in need thereof, acomposition comprising at least one polar, hydrophilic stimulant prodrugof the present technology that can decrease the pharmacological activityof the stimulant when the composition is used in a manner inconsistentwith the manufacturer's instructions.

Another embodiment of the present technology is a method for reducing orpreventing the euphoric effect of a stimulant, comprising consuming acomposition comprising at least one polar, hydrophilic stimulant prodrugof the present technology that can decrease the pharmacological activityof the stimulant when the composition is used in a manner inconsistentwith the manufacturer's instructions.

Another embodiment of the present technology is any of the precedingmethods wherein the stimulant composition used is adapted for oraladministration, and wherein the stimulant prodrug is resistant torelease the stimulant from the polar hydrophilic moiety when thecomposition is administered parenterally, such as intranasally orintravenously. Preferably, the stimulant may be released from the polarhydrophilic moiety in the presence of acid and/or enzymes present in thestomach, intestinal tract, or blood serum. Optionally, the stimulantcomposition used may be in the form of a tablet, capsule, oral solution,oral suspension, thin strip or other oral dosage form discussed herein.

For one or more of the recited methods, the composition of the presenttechnology used may yield a therapeutic effect without substantialeuphoria. Preferably, the stimulant composition of the presenttechnology can provide a therapeutically equivalent AUC when compared tothe stimulant alone but does not provide a C_(max) which results ineuphoria or an equivalent C_(max).

Another embodiment of the present technology is a method for reducing orpreventing abuse of stimulants such as amphetamine comprising orallyadministering a stimulant prodrug composition of the present technologyto a patient, wherein said composition comprises at least one polar,hydrophilic stimulant prodrug of the present technology that candecrease the pharmacological activity of the stimulant when thecomposition is used in a manner inconsistent with the manufacturer'sinstructions.

Another embodiment is a method for reducing or preventing the euphoriceffect of a stimulant comprising orally administering a stimulantprodrug composition of the present technology to a patient in needthereof, wherein said composition comprises at least one polar,hydrophilic prodrug of the stimulant of the present technology that candecrease the pharmacological activity of the stimulant when thecomposition is used in a manner inconsistent with the manufacturer'sinstructions.

For one or more of the recited methods of the present technology, thefollowing properties may be achieved through conjugating amphetamine toa polar hydrophilic group. In one embodiment, the cardiovasculartoxicity or stress of the polar hydrophilic prodrug of amphetamine ofthe present technology may be lower than that of the amphetamine whenthe amphetamine is delivered in its unconjugated state, as a compoundconjugated to a standard amino acid, or as a salt thereof. In anotherembodiment, the possibility of behavioral deterioration is reduced oreliminated. In another embodiment, the possibility of abuse byintranasal administration is reduced or eliminated. In anotherembodiment, the possibility of abuse by intravenous administration isreduced or eliminated.

Another embodiment of the present technology provides methods oftreating various diseases or conditions requiring the stimulation of thecentral nervous system (CNS) comprising administering compounds orcompositions of the present technology which, optionally, furthercomprise commonly prescribed active agents for the respective illness ordisease. For instance, one embodiment of the invention comprises amethod of treating attention deficit hyperactivity disorder (ADHD)comprising administering to a patient at least one polar, hydrophilicprodrug of amphetamine of the present technology. Another embodimentprovides a method of treating attention deficit disorder (ADD)comprising administering to a patient compounds or compositions of theinvention.

Another embodiment of the invention provides a method of treatingnarcolepsy comprising administering to a patient compounds orcompositions of the presently described technology.

The presently described technology and its advantages will be betterunderstood by reference to the following examples. These examples areprovided to describe specific embodiments of the present technology. Byproviding these specific examples, the applicants do not limit the scopeand spirit of the present technology. It will be understood by thoseskilled in the art that the full scope of the presently describedtechnology encompasses the subject matter defined by the claimsappending this specification, and any alterations, modifications, orequivalents of those claims.

Example 1 Comparative Study of Pharmacokinetic Parameters of Releasedd-Amphetamine Following Administration of a Polar Hydrophilic Prodrug ofthe Non-Standard Amino Acid Type (hArg-Amp) and a Standard Amino AcidConjugate (Vyvanse™, Lys-Amp)

The pharmacokinetic parameters of d-amphetamine following oraladministration of a non-standard amino acid conjugate of the presenttechnology and a standard amino acid conjugate, Vyvanse™ (Lys-Amp),commercially available from Shire, Incorporated of Wayne, Pa. arestudied in this example. The non-standard amino acid conjugate used inthis example is the hydrochloride salt of hArg-Amp. The results arerecorded in the table below:

TABLE 1 Non-standard amino Acid Parameter % amp¹ Vyvanse ™ % total Amp²AUC_(0-8 h) 94% 100% AUC_(0-4 h) 77% 100% AUC_(inf) 95% 100% C_(max) 76%100% T_(max) 400% 100% ¹Percent amphetamine released relative toVyvanse ™ (at an equimolar concentration of amphetamine contained in thenon-standard amino acid prodrug compared to the total amphetaminecontained in Vyvanse ™) ²Percent amphetamine relative to 50 mg Vyvanse ™dose

The study shows that the C_(max) of a prodrug of the preset technologyis significantly lower than that of Vyvanse™, a standard amino acidconjugate of d-amphetamine, which can lead to lower cardiovasculareffects (blood pressure, heart rate). Quick release (higher C_(max)) ofamphetamine has already demonstrated significant increases in bloodpressure and heart rate. In certain patient populations, thesecardiovascular side effects can be dose limiting or can cause thetermination of stimulant therapy.

The pharmacokinetic parameters of d-amphetamine following parentaladministration of hArg-Amp and d-amphetamine are also studied. The studyshows that little release of amphetamine (<25%) happens when hArg-Amp istaken through parental routes (intranasal, intravenous) due todifferences in enzymes encountered in the gut versus other routes. WhenAdderall X® or other controlled release formulations of amphetamine areinjected or snorted, the pharmacokinetic parameters of the amphetamineare significantly altered and an individual can use these changes toproduce euphoria.

Example 2 Preparation of Boc-hArg(NO₂)-Amp

Boc-hArg(NO₂)—OH (2.667 g, 8 mmol) was dissolved in DMF (25 ml). EDCI(2.30 g, 12 mmol), NHS (1.012 g, 8.8 mmol), d-amphetamine (1.269 g, 9.6mmol) and DIEA (1.138 g, 8.8 mmol) were then added sequentially. Theclear reaction mixture was stirred at room temperature for 16 hrs. Thereaction mixture was quenched with pH 3 water (150 ml), and the productwas extracted with EtOAc (3×50 ml). The combined extracts were washedwith pH 3 water followed by saturated NaCl. The EtOAc layer was driedover anhydrous MgSO₄. The product was recrystallized from EtOAc-Hexanetwo times to give 2.36 g of desired protected product.

The product was analyzed using ¹H NMR (DMSO-d₆) δ. The result shows0.9-1.1 (m, 3H, Amp CH₃), 1.1-1.2 (m, 2H, hArg γ CH₂), 1.2-1.5 (m, 13H,Boc CH₃, hArg β,δ CH₂), 2.55-2.75 (m, 2H, Amp β CH₂), 3.1 (m, 2H, hArg εCH₂), 3.75 (m, 1H, Amp α CH), 3.95 (m, 1H, hArg α CH), 6.65 (t, 1H, hArgguanidino NH), 7.1-7.3 (m, 5H, Amp Ar—H), 7.6-8.2 (br m, 2H, hArgguanidine NH and amide NH), 8.5 (br s, 1H, hArg NH—NO₂). These resultsare consistent with the proposed structure.

Example 3 Preparation of hArg-Amp-2HCl (l-homoarginine-d-amphetaminedihydrochloride)

Boc-hArg(NO₂)-Amp (1.5 g) was dissolved in HPLC grade MeOH (120 ml) andto the clear solution was added the Pd—C catalyst (10%, Aldrich). Asmall stir bar was placed in the flask and the reaction mixture wasstirred under a slow stream of hydrogen overnight after incorporatingthe 5-6N HCl in 2-propanol solution (1.5 ml). After the overnightreaction, the solution was filtered and the solvent evaporated. Thewhite crystalline product was dried under vacuum to give 1.61 g of theBoc-hArg-Amp intermediate product.

The product (1.6 g) was dissolved in 80 ml of HPLC grade MeOH, and 5-6NHCl in 2-propanol (3.2 mL) was added to the solution. The reactionmixture was stirred overnight, solvent removed and re-dissolved inminimum amount of MeOH. The final product was crashed out with MTBE, anddried under vacuum at 30° C. for about 20 hours to yield 1.12 g of awhite powder.

The white powder was analyzed using ¹H NMR (DMSO-d₆) δ. The result shows0.9-1.1 (m, 3H, Amp CH₃), 1.1-1.2 (m, 2H, hArg γ CH₂), 1.35 (m, 2H, hArgβ CH₂), 1.55 (m, 2H, hArg δ CH₂), 2.75 (d, 2H, Amp β CH₂), 3.0 (m, 2H,hArg ε CH₂), 3.75 (m, 1H, Amp α CH), 4.05 (m, 1H, hArg α CH), 7.1-7.2(m, 5H, Amp Ar—H), 7.2-7.8 (br m, 3H, amide NH, HCl), 8.0 (t, 1H, hArgguanidino NH), 8.2 (br s, 2H, amide or guanidino NH₂), 8.75 (d, 1H,amide NH); ¹³C NMR (DMSO-d₆) δ 21.08 (Amp CH₃), 21.36 (hArg γ), 28.23(hArg δ), 32.28 (hArg β), 40.18 (Amp β), 42.19 (hArg ε), 46.88 (Amp α),52.23 (hArg α), 126.54 (p-Ar), 128.52 (m-Ar), 129.60 (o-Ar), 139.34(Ar), 157.61 (C═O), 167.95 (guanidino C); M+1=306. These results areconsistent with the proposed structure.

Example 4 Preparation of Cit-Amp.HCl (l-citrulline-d-amphetaminehydrochloride)

Boc-Cit-OH (0.500 g, 1.82 mmol) was dissolved in anhydrous THF. To thissolution was added NHS (0.209 g, 1.82 mmol) followed by DCC (0.376 g,1.82 mmol). Resulting slurry was stirred at ambient temperatureovernight. In a separate flask, d-amphetamine sulfate (0.306 g, 0.83mmol) was suspended in THF (10 ml) and NMM (0.34 ml, 3.64 mmol) wasadded. The activated ester was filtered directly into the amphetaminesuspension and the resulting suspension was stirred overnight. Thereaction was quenched with 5% NaHCO₃ and IPAC for 45 min. Organicsolvent was then removed. The aqueous layer was then extracted 3 timeswith IPAC and the combined organics were washed with 5% acetic acid, 5%NaHCO₃ and 5% NaCl. The organic layer was then dried over Na₂SO₄ andsolvent was removed. Crude product was re-crystallized usingIPAC/heptane to yield 200 mg of a white solid. HPLC: column: YMC ODS-AQ,5 μm, 120 Å, 4.6×250 mm; mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN;method: 0-15 min.: 85/15→60/40, 15-25 min.: 60/40→0/100; flow rate: 1mL/min.; UV detection: 230 nm; retention time: 8.06 min.

10 ml of 4N HCl in dioxane were added to the 200 mg (0.200 g)Boc-Cit-Amp. The mixture was stirred at room temperature for 6 hours andsolvent was removed.

Example 5 Preparation of hCit-Amp.HCl (l-homocitrulline-d-amphetaminehydrochloride)

Procedure as described for citrulline. However, 1,4-dioxane was usedduring amino acid activation and coupling reaction instead of THF. Crudeproduct was purified via column chromatography (0-6.5% MeOH/DCM) to give201 mg (0.49 mmol) of Boc-l-hCit-d-amphetamine (based on 500 mg ofBoc-l-hCit-OH).

The Boc-protected Boc-l-hCit-d-amphetamine (110 mg, 0.27 mmol) wascooled in an ice-bath and 10 mL of chilled 4 N HCl/dioxane were added.The mixture was stirred for 4 h and solvent was evaporated to drynessyielding 92 mg (0.27 mmol) of l-hCit-d-amphetamine.HCl. HPLC: column:YMC ODS-AQ, 5 μm, 120 Å, 4.6×250 mm; mobile phase: A=0.1% TFA/H₂O,B=0.1% TFA/MeCN; method: 0-15 min.: 85/15→60/40, 15-25 min.:60/40→0/100; flow rate: 1 mL/min.; UV detection: 230 nm; retention time:8.92 min.

Example 6 Preparation of hyPro-Amp.HCl (2-hydroxyproline-d-amphetaminehydrochloride)

Z-l-hyPro(tBu)-OH (1.000 g, 3.11 mmol) was dissolved in 15 mL ofanhydrous THF. NHS (0.358 g, 3.11 mmol) was added and the solution wasstirred for 5 min. DCC (0.642 g, 3.11 mmol) was then added and themixture stirred overnight at ambient temperature. In a separate flask,d-amphetamine sulfate (0.521 g, 1.41 mmol) was suspended in 15 mL ofanhydrous THF and NMM (0.68 mL, 6.22 mmol) was added. The mixture wasstirred for 10 min. Subsequently, the prior prepared succinimidyl esterwas charged to the suspension through a sintered funnel and the mixturewas stirred overnight. The reaction was quenched with 5% NaHCO₃ solution(75 mL). IPAC (25 mL) was added and the solution stirred for 45 min. Themixture was concentrated by evaporating most of the organic solvents.The aqueous layer was extracted with IPAC (3×100 mL). The combinedorganics were washed with 5% HOAc (1×100 mL), 5% NaHCO₃ (1×100 mL) and5% NaCl solution (2×100 mL), dried over Na₂SO₄ and evaporated todryness. Crude product was dissolved in 10 mL of Ac₂O at 60° C. and 10mL water were added while hot. The mixture was kept overnight at ambienttemperature. White crystals formed which were filtered off, rinsed withwater and dried in high vacuum to yield 877 mg (2.00 mmol) ofZ-l-hyPro(tBu)-d-amphetamine.

Fully protected Z-l-hyPro(tBu)-d-amphetamine (500 mg, 1.14 mmol) wasdissolved in 10 mL of MeOH. Pd/C (10 w.t.-% Pd, 250 mg) was added andthe mixture stirred overnight in hydrogen atmosphere at ambienttemperature. The suspension was filtered through Celite® and solvent wasevaporated to dryness. Crude product was purified via columnchromatography (0-2.5% MeOH/DCM) to give 96 mg (0.32 mmol) ofl-hyPro(tBu)-d-amphetamine.

Hydroxyl-protected l-hyPro(tBu)-d-amphetamine (96 mg, 0.32 mmol) wascooled in an ice-bath and 5 mL of chilled TFA were added. The ice-bathwas removed and the mixture was stirred overnight. The solvent wasevaporated and the remaining residue was dissolved in 4 N HO/dioxane.This process was repeated three times. The product was dried in highvacuum to yield 90 mg (0.32 mmol) of l-hyPro-d-amphetamine.HCl. HPLC:column: YMC ODS-AQ, 5 μm, 120 Å, 4.6×250 mm; mobile phase: A=0.1%TFA/H₂O, B=0.1% TFA/MeCN; method: 0-15 min.: 85/15→60/40, 15-25 min.:60/40→0/100; flow rate: 1 mL/min.; UV detection: 230 nm; retention time:9.61 min.

Example 7 Preparation of Arg(NO2)-Amp.2HCl(l-arginine(NO2)-d-amphetamine dihydrochloride)

Procedure as described for citrulline. Crude product was purified viacolumn chromatography (0-3.5% MeOH/DCM) to give 471 mg (1.08 mmol) ofBoc-l-Arg(NO₂)-d-amphetamine (based on 1.000 g of Boc-l-Arg(NO₂)—OH).

Boc-protected Boc-Arg(NO₂)-d-amphetamine was deprotected using theprocedure described for homocitrulline yielding 442 mg (1.08 mmol) ofl-Arg(NO₂)-d-amphetamine.HCl. HPLC: column: YMC ODS-AQ, 5 μm, 120 Å,4.6×250 mm; mobile phase: A=0.1% TFA/H₂O, B=0.1% TFA/MeCN; method: 0-15min.: 85/15→60/40, 15-25 min.: 60/40→0/100; flow rate: 1 mL/min.; UVdetection: 230 nm; retention time: 9.21 min.

Example 8 Preparation of Lysinol-Co-Amp

Boc-l-Lys(Z)-ol (500 mg, 1.36 mmol) was dissolved in 10 mL of anhydrousdioxane. CDI was added and the mixture stirred overnight at ambienttemperature. Solvent was evaporated to dryness and the remaining oilyresidue was dissolved in 15 mL of anhydrous THF. Amphetamine sulfate(277 mg, 0.75 mmol) and Et₃N (0.40 mL, 2.86 mmol) were added and themixture was stirred overnight at 50° C. The reaction was quenched withwater and the aqueous layer extracted with IPAC (3×75 mL). The combinedorganics were washed with 5% HOAc, sat. NaHCO₃, sat. NaCl and 5% NaClsolution and dried over Na₂SO₄. Solvents were evaporated to drynessyielding Boc-l-Lys(Z)-OCONH-d-amphetamine as a white foam. HPLC: column:YMC ODS-AQ, 5 μm, 120 Å, 4.6×250 mm; mobile phase: A=0.1% TFA/H₂O,B=0.1% TFA/MeCN; method: 0-15 min.: 85/15→60/40, 15-25 min.:60/40→0/100; flow rate: 1 mL/min.; UV detection: 230 nm; retention time:20.59 min.

Example 9 Preparation of Carn-Amp (O-acetyl-l-carnitine-d-amphetaminechloride)

O-Acetyl-l-carnitine.Cl (1.000 g, 4.17 mmol) was dissolved in 12.5 mL ofa mixture of DMF/dioxane/water (2:2:1). NHS (0.528 g, 4.59 mmol) and DCC(0.947 g, 4.59 mmol) were added and the mixture was stirred overnight atambient temperature. Solvents were evaporated and the remaining residuewas dried overnight in high vacuum. The crude succinimidyl esterintermediate was dissolved in 20 mL of anhydrous DMF. Amphetaminesulfate (0.700 g, 1.90 mmol) and NMM (0.92 mL, 8.34 mmol) were added andthe mixture stirred overnight. Solvent was evaporated to dryness and theremaining residue was leached with IPA. Solvent was evaporated to yieldCarn-d-amphetamine.

Example 10 Pharmacokinetic Study of hArg-Amp vs. Lys-Amp

Male Sprague-Dawley rats were fasted overnight and dosed by oral gavagewith either l-homoarginine-d-amphetamine (hArg-Amp) orl-lysine-d-amphetamine (Vyvanse™, Lys-Amp). Water was provided adlibitum. Doses were calculated at an equivalent 1.5 mg/kg freebaseequivalent of d-amphetamine. Plasma concentrations of d-amphetamine weremeasured using ELISA (Neogen Corp. Lexington, Ky.).

Mean plasma concentration curves (n=5) of d-amphetamine released byl-homoarginine-d-amphetamine or l-lysine-d-amphetamine are shown inFIG. 1. Pharmacokinetic (PK) parameters of this study are listed inTable 2.

TABLE 2 Pharmacokinetic Properties of hArg-Amp and Lys-Amp Vehicle % AUCTmax Cmax % Tmax % Cmax Lys-Amp 100% 3 h 44 ng/ml 100% 100% hArg-Amp 99%4 h 44 ng/ml 133% 100%

This pharmacokinetic (PK) study clearly demonstrates a shift in theT_(max) for the polar hydrophilic prodrug of the non-standard amino acidtype (hArg-Amp) compared to the standard amino acid (Lys-Amp). Thisshift may be due to a reduction in the rate of enzymatic hydrolysis ofthe amide bond of the non-standard amino acid attached to amphetaminevs. the standard amino acid attached to amphetamine.

FIGS. 2-4 represent different ways to view the data reflected in FIG. 1and Table 2. As further discussed below, these figures highlight thedifferences of hArg-Amp over Lys-Amp during the first several hours.

FIG. 2 demonstrates the relative blood levels of d-amphetamine releasedfrom both Lys-Amp and hArg-Amp. The graph shows that equivalent bloodlevels do not occur until later time points and that blood levels do notappear to spike or have a more significant C_(max) than Lys-Amp. Theamount of d-amphetamine released from hArg-Amp is gradual and maintainsa more steady concentration over the duration of the study than didLys-Amp. In contrast, Lys-Amp blood levels of released d-amphetamine“spiked” at 3 hours and cleared more quickly than the blood levelsobtained from hArg-Amp.

FIGS. 3 and 4 show the difference in blood levels obtained from thestudy described in FIG. 2. As is shown, the initial blood levels forboth conjugates (Lys-Amp and hArg-Amp) are very different, with hArg-Ampreleasing amphetamine at a more gradual rate. These differences in bloodlevels become less during the more critical duration of action forstimulant treatments and more importantly, the differences are greateragain at later time points suggesting that hArg-Amp maintains a moreconsistent dose of amphetamine when compared to Lys-Amp. The longerduration of release for hArg-Amp would suggest a much lower opportunityfor behavioral deterioration to occur.

Other oral studies have been conducted in a similar fashion and aresummarized in Table 3 below. The average PK results for four (4) oralstudies (n=30 per vehicle) are recorded in FIG. 5:

TABLE 3 Average Results of 6 Oral Studies (n = 30 per compound) Vehicle% AUC Tmax % Tmax % Cmax % AUC 0-4 h Lys-Amp 100%   1 h 100% 100% 100%hArg-Amp 81% 2-4 h 200-400% 69% 67%

Example 11 Comparative Biological Study of Lys-Amp and Cit-Amp

To compare the amount of release of d-amphetamine among various polarhydrophilic prodrugs, l-citrulline-d-amphetamine (Cit-Amp) was dosedwith Lys-Amp in another oral pharmacokinetic study. Mean plasmaconcentration curves (n=5) of d-amphetamine released by Cit-Amp andLys-Amp are shown in FIG. 6. Pharmacokinetic parameters of this studyare listed in Table 4.

Direct comparison of polar hydrophilic prodrugs especially non-standardamino acid conjugates of amphetamine (Cit and hArg) demonstrate thesignificant ability to shift or change the pharmacokinetic propertiesversus the standard amino acids. All non-standard amino acids studiedreleased amphetamine in an amount greater than 50%. Homoarginine showedC_(max) levels far below that of lysine and homoarginine and citrullinesignificantly shifted the T_(max) compared to Lys-Amp. These changes tothe pharmacokinetic properties of amphetamine when conjugated tonon-standard amino acids represent clinically significant changes notdescribed or demonstrated by Lys-Amp nor described or demonstrated byother standard amino acids.

TABLE 4 Oral Properties of Lys-Amp and Cit-Amp Vehicle % AUC Tmax Cmax %Tmax % Cmax Lys-Amp 100%  1 h  59 ng/ml 100% 100% Cit-Amp 95%  15 m 129ng/ml 25% 219%

Example 12 Pharmacokinetic Study of Lys-Amp, hCit-Amp and hArg(NO₂)-Amp

To compare the amount of release of d-amphetamine among various polarhydrophilic prodrugs, l-homocitrulline-d-amphetamine (hCit-Amp) andl-homoarginine (NO₂)-d-amphetamine (hArg(NO₂)-Amp) were dosed withLys-Amp in another oral pharmacokinetic study. Mean plasma concentrationcurves (n=5) of d-amphetamine released by the amphetamine prodrugs areshown in FIG. 7. Pharmacokinetic parameters of this study are listed inTable 5.

TABLE 5 Oral Properties of Lys-Amp, hCit-Amp, and hArg(NO₂)-Amp Vehicle% AUC Tmax Cmax % Tmax % Cmax Lys-Amp 100% 1 h 54 ng/ml 100% 100%hCit-Amp 78%  1 m 57 ng/ml NA 105% hArg(NO₂)-Amp 69% 1 h 59 ng/ml NA109%

Example 13 Intranasal Study of Amp, Lys-Amp and hArg-Amp

Male Sprague-Dawley rats were fasted overnight and dosed by intranasaladministration with either hArg-Amp, Lys-Amp or d-amphetamine. Doseswere calculated at an equivalent 1.5 mg/kg freebase equivalent ofd-amphetamine. Plasma concentrations of d-amphetamine were measuredusing ELISA. Mean plasma concentration curves (n=5) of d-amphetaminereleased by hArg-Amp or Lys-Amp are shown in FIG. 8. Pharmacokineticparameters of this study are listed in Table 6. No significant release(<50%) was observed in either hArg-Amp or Lys-Amp and less release wasobserved within the first hour of administration (<25%). Observed levelsfrom Lys-Amp are significantly higher than previously published data.

TABLE 6 Intranasal Properties of d-Amp, hArg-Amp and Lys-Amp Vehicle %AUC Tmax Cmax % Tmax % Cmax d-amp 100%  5 m 779 ng/ml 100% 100% hArg-Amp42% 0.5 h  71 ng/ml 600% 9% Lys-Amp 36%   3 h  79 ng/ml 3600% 10%

Example 14 Intravenous Study of d-Amp, hArg-Amp, Lys-Amp

Male Sprague-Dawley rats were dosed by intravenous administrationthrough the tail vein with hArg-Amp, Lys-Amp or d-amphetamine. Doseswere calculated at an equivalent 1.5 mg/kg freebase equivalent ofd-amphetamine. Plasma concentrations of d-amphetamine were measuredusing ELISA. Mean plasma concentration curves (n=5) of d-amphetaminereleased by hArg-Amp or Lys-Amp are shown in FIG. 9. Pharmacokineticparameters of this study are listed in Table 7. No significant release(<15%) was observed in either hArg-Amp or Lys-Amp though hArg-Amp wassignificantly less. Observed levels from Lys-Amp are significantlyhigher than previously published data. The initial spike ind-amphetamine released from hArg-Amp cleared quickly.

TABLE 7 Intravenous Properties of d-Amp, hArg-Amp and Lys-Amp Vehicle %AUC Tmax Cmax % Tmax % Cmax d-amp 100%  5 m 554 ng/ml 100% 100% hArg-Amp8%  5 m  68 ng/ml 100% 12% Lys-Amp 14% 15 m  79 ng/ml 100% 14%

Results of the studies in above examples clearly show an unexpectedchange in the oral pharmacokinetic properties by using polar hydrophilicprodrugs. By changing the polar hydrophilic group attached toamphetamine, the conjugates are able to shift T_(max) (earlier orlater), modify curve shape, lower C_(max), and raise C_(max). Inaddition, the shift in T_(max) for hArg-Amp may be clinicallysignificant in that many of the cardiovascular side effects and toxicityare related to T_(max) and C_(max). The results demonstrate that byusing these polar hydrophilic group, a shift in the T_(max), with alower C_(max) occurs without changing AUC significantly. In addition,the slope of uptake of hArg-Amp vs. Lys-Amp appears to be more gradualthus leading to a slower onset which could further alleviate sideeffects.

The amphetamine conjugates listed above of the present technologydemonstrates that by using polar hydrophilic prodrugs, a shift in theT_(max) occurs while still retaining AUC and potential clinical effect.By using polar hydrophilic prodrugs, we are able to demonstrate thathArg-Amp show little release via the IN (intransal) or IV (intravenous)route yet still maintain a similar AUC.

The polar, hydrophilic amphetamine prodrug of the present technology ischemically stable to in vitro hydrolysis of the amide linkage to preventtampering or removing the amphetamine prior to oral ingestion. Also, thecontrolled release of amphetamine through oral administration of thepolar, hydrophilic amphetamine prodrug of the present technology is aninherent property of the molecule, not related to the formulation.Therefore, the prodrug of the present technology can be easilyformulated to different dosage forms.

The invention is now described in such full, clear, concise and exactterms as to enable any person skilled in the art to which it pertains,to practice the same. It is to be understood that the foregoingdescribes preferred embodiments of the invention and that modificationsmay be made therein without departing from the spirit or scope of theinvention as set forth in the appended claims.

1. A method for treating a patient having a disorder or conditionrequiring the stimulation of the central nervous system of the patient,comprising orally administering to the patient a pharmaceuticallyeffective amount of at least one conjugate, a salt of the conjugatethereof, or a combination thereof, wherein the conjugate comprisesamphetamine and homoarginine.
 2. The method of claim 1, wherein the atleast one conjugate is l-homoarginine-d-amphetamine.
 3. The method ofclaim 1, wherein said step of orally administering comprisesadministering a tablet, a capsule, a caplet, a troche, a lozenge, anoral powder, an oral solution, an oral film, a thin strip, or an oralsuspension.
 4. The method of claim 1, wherein the conjugate isadministered in the form of a salt.
 5. The method of 4, wherein the saltis a mesylate, a hydrochloride salt, a sulfate, an oxalate, a triflate,a citrate, a malate, a tartrate, a phosphate, a nitrate, a benzoate, anacetate, a carbonate, a hydroxide, a sodium salt, a potassium salt, amagnesium salt, a calcium salt, a zinc salt, an ammonium salt, or amixture thereof.
 6. The method of claim 1, comprising administering adosage form containing from about 1 mg to about 1000 mg of theconjugate, the salt thereof, or the combination thereof.
 7. The methodof claim 1, comprising administering a dosage form containing from about5 mg to about 250 mg of the conjugate, the salt thereof, or thecombination thereof.
 8. The method of claim 1, comprising administeringa dosage form containing from about 10 mg to about 100 mg of theconjugate, the salt thereof, or the combination thereof.
 9. The methodof claim 1, wherein the conjugate, the salt thereof, or the combinationthereof is in an amount sufficient to provide a therapeuticallybioequivalent Area Under the Curve (AUC) when compared to amphetaminealone, but does not provide a C_(max) spike.
 10. The method of claim 1,wherein the conjugate, the salt thereof, or the combination thereof isin an amount sufficient to provide a therapeutically bio equivalent AUCwhen compared to amphetamine alone, but does not provide an equivalentC_(max).
 11. The method of claim 1, wherein the disorder or condition isattention deficit hyperactivity disorder, attention deficit disorder,obesity, narcolepsy, appetite suppression, depression, anxiety,wakefulness, or a combination thereof.
 12. The method of claim 11,wherein the disorder or condition is obesity.
 13. The method of claim11, wherein the disorder or condition is appetite suppression.
 14. Themethod of claim 11, wherein the disorder or condition is depression. 15.The method of claim 11, wherein the disorder or condition is narcolepsy.16. The method of claim 11, wherein the disorder or condition isattention deficit hyperactivity disorder.
 17. The method of claim 11,wherein the disorder or condition is attention deficit disorder.
 18. Themethod of claim 3, wherein the step of orally administering comprisesadministering an oral film.
 19. The method of claim 3, wherein the stepof orally administering comprises administering a thin strip.